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Published ahead of print on April 1, 2005, doi:10.1164/rccm.200409-1257OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 1, July 2005, 74-84

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Submitted on September 22, 2004
Accepted on March 30, 2005

Steroid Resistant Inflammation in a Rat Model of COPD is Associated with a Lack of NF-{kappa}B Activation

Mark A Birrell1, Sissie Wong1, David J Hele1, Kerryn McCluskie1, Elizabeth Hardaker1, and Maria G Belvisi1*

1 Respiratory Pharmacology Group, Imperial College, National Heart and Lung Institute, London, United Kingdom

* To whom correspondence should be addressed. E-mail: m.belvisi{at}imperial.ac.uk.

Rationale: Emphysema is one component of COPD, a respiratory disease currently increasing in prevalence worldwide. The mainstay therapy adopted to treat patients with COPD is glucocorticoids; unfortunately this treatment has limited impact on disease symptoms or underlying airway inflammation. Objective: There is an urgent need to develop therapies that modify both the underlying inflammation, thought to be involved in the disease progression, and the structural changes in the emphysematous lung. Methods: We have characterised an elastase driven model of experimental emphysema in the rat that demonstrates COPD-like airway inflammation and determined the impact of a clinically relevant glucocorticoid. Measurements and main results: We observed an increase in lung neutrophils, lymphomononuclear cells, mucus production and inflammatory cytokines. Also present were increases in average air space area which is associated with emphysema-like changes in lung function, such as increased residual volume and decrease flow, which was maintained for up to 10 weeks. In addition, this manuscript demonstrates that elastase-induced airway neutrophilia is steroid resistant. Interestingly, the inflammation observed after elastase was found to be temporally associated with a lack of NF-{kappa}B pathway activation. This apparent NF-{kappa}B independent inflammation may explain why treatment with a glucocorticoid was ineffective in this pre-clinical model and could suggest parallels in the steroid resistant human disease. Conclusion: We believe that this model, in addition to its suitability for testing therapies that may modify existing emphysema, could be useful in the search for new therapies to reduce the steroid resistant airway inflammation evident in COPD.
Key words: Rodent, inflammation, lung, steroid




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